Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression - Involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis
Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression - Involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis
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DOI：
10.1161/01.atv.0000131784.50633.4f
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发表时间：
2004-07-01
影响因子：
8.7
通讯作者：
Libby, P
中科院分区：
文献类型：
--
作者：
Sugiyama, S;Kugiyama, K;Libby, P
目的：由于内皮细胞丢失引起的冠状动脉斑块的表面侵蚀引起急性冠状动脉综合征（ACS）。在人冠状动脉粥样硬化的侵蚀部位的巨噬细胞呈现髓过氧化物酶（MPO），一种产生次氯酸（HOCl）的酶。方法和结果-激活的MPO阳性巨噬细胞或外源性HOCl促进内皮细胞（EC）从“Matrigel”基质的体外分离。病理生理相关浓度的HOCl以浓度依赖性方式引起EC死亡：HOCl（20 - 50 mumol/L）诱导EC快速收缩，核浓缩和EC单层破坏，而浓度>100 mumol/L立即诱导EC质膜起泡而不收缩。HOCl（30 ~ 50 mumol/L）也可诱导EC中caspase-3活化、聚ADP-核糖聚合酶降解和DNA梯状化。HOCl迅速降低内皮Bcl-2和诱导细胞色素C的释放，表明HOCl激活凋亡EC死亡，部分通过线粒体损伤。细胞内谷胱甘肽（GSH）水平的增加后，与GSH单乙酯（GSH-β）处理减弱HOCl诱导的EC凋亡。亚致死浓度的HOCl（1.0 ~ 15 mumol/L）可增加EC中的组织因子，而GSH-γ处理限制了HOCl的这种作用。结论HOCl可通过凋亡或肿瘤细胞死亡途径引起EC死亡和脱落，亚致死浓度的HOCl可增加内皮组织因子。这些结果表明，动脉粥样硬化内皮下MPO阳性巨噬细胞源性HOCl可能通过促进浅表糜烂和增加血栓形成而参与ACS。
Objective - Superficial erosion of coronary plaques due to endothelial loss causes acute coronary syndromes (ACS). Macrophages at erosive sites of human coronary atheroma present myeloperoxidase (MPO), an enzyme that produces hypochlorous acid (HOCl).Methods and Results - Activated MPO-positive macrophages or exogenous HOCl promoted detachment of endothelial cells (EC) from "Matrigel" substrata in vitro. Pathophysiologically relevant concentrations of HOCl caused EC death in a concentration-dependent manner: HOCl (20 to 50 mumol/L) induced rapid shrinkage of EC with nuclear condensation and disruption of EC monolayers, whereas concentrations >100 mumol/L immediately induced blebbing of the EC plasma membrane without shrinkage. HOCl ( 30 to 50 mumol/L) also induced caspase-3 activation, poly (ADP-ribose) polymerase degradation, and DNA laddering in EC. HOCl rapidly decreased endothelial Bcl-2 and induced cytochrome-C release, indicating that HOCl activates apoptotic EC death, partially via mitochondrial damage. Increased intracellular glutathione (GSH) levels after treatment with GSH monoethyl ester (GSH-MEE) attenuated HOCl-induced EC apoptosis. Sublethal concentrations of HOCl (1.0 to 15 mumol/L) increased tissue factor in EC and GSH-MEE treatment limited this effect of HOCl.Conclusions - HOCl can provoke EC death and desquamation by either apoptotic or oncotic cell-death pathways, and sublethal concentrations of HOCl can increase endothelial tissue factor. These results show that MPO-positive macrophage-derived HOCl in the subendothelium of atheromata may participate in ACS by promoting superficial erosion and increasing thrombogenicity.